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Biomedical subjects

A J Cooper

Publications and source records attributed to A J Cooper.

At least 19 recordsLinked to original sources
PubMed2006

Meglumine Eicosapentaenoic acid (MeEPA) a new soluble omega-3 fatty acid formulation: in vitro bladder cancer cytotoxicity tests in combination with epirubicin and mitomycin.

OBJECTIVE: To determine if Meglumine-Eicosapentaenoic Acid (MeEPA) acts synergistically with epirubicin and mitomycin to enhance cytotoxicity towards bladder cancer cell lines in vitro. MATERIALS AND METHODS: Bladder cancer cells were exposed to MeEPA in combination with epirubicin or mitomycin. Residual viable cell biomass was estimated with the methyl-thiazoldiphenyl tetrazolium (MTT) assay following drug exposure. Drug interaction was analysed using median effect analysis to determine levels of synergism. RESULTS: Most combinations of MeEPA with both epirubicin and mitomycin showed a high-level of synergism. At high doses, drug precipitation adversely affected MTT assay analysis suggesting antagonism of action. However, the predominant pattern was of synergism for most dose combinations tested. CONCLUSION: Bladder cancer treated by endoscopic resection alone is subject to high recurrence rates. Post-operative intravesical instillation of epirubicin and mitomycin can halve recurrence rates, but there is no evidence that disease progression to invasive bladder cancer is altered. Thus, optimisation of current treatment strategies is required. The anti-tumour activity of fatty acids is well established and MeEPA is a new, soluble formulation with the potential to enhance intravesical drug efficacy.

Antibiotics, Antineoplastic↗
PubMed2006

Seminal prostasomes inhibit the angiogenesis activity of rat aortic rings.

Prostasomes are organelles secreted by prostatic epithelial cells, and are believed to have a role in fertility and prostatic disease. They are known to influence sperm motility and the acrosome reaction, and are thought to have a role in cell transformation, immunosuppression, proliferation, facilitation of local invasion, and angiogenesis. Previously, we have demonstrated the inhibitory effect of prostasomes derived from human semen on angiogenesis using HUVEC cells grown on matrigel. In this study, we use the rat aortic ring assay system, arguably a closer reflection of the in vivo situation. Quantification was by a spectrophotometric method, and underlying mechanisms assessed. Prostasomes demonstrated a clear inhibition of angiogenesis, and this effect persisted after heat treatment of prostasomes to denature protein. This fits with other known effects of prostasomes known to be due to the membrane lipid component, which is unusually high in sphingomyelin and cholesterol.

Animals↗
PubMed2006

Furosemide reverses multidrug resistance status in bladder cancer cells in vitro.

BACKGROUND: Multidrug resistance (MDR) has a potentially serious influence on cancer treatment and should be taken into consideration in the design and application of therapeutic regimens. It is mediated through the activity of cellular pumps. AIM: To investigate whether furosemide, itself a pump-blocker, reverses MDR in an in vitro model. MATERIALS AND METHODS: An MDR bladder cancer cell line (MGH-u 1R) and its parental (drug sensitive) clone were exposed to epirubicin and furosemide, with the concentration of one drug fixed and that of the other serially diluted in a 96-well plate format. Both drugs formed the variable component in separate experiments. After a 1-h exposure, the cells were washed and replenished with fresh medium. To examine the toxicity of epirubicin and furosemide separately and in combination, monotetrazolium-based assays were carried out. Intracellular epirubicin distribution was assessed by confocal microscopy as a second index of resistance status after in vitro exposure. RESULTS: MGH-u 1R cells incubated with furosemide showed distribution of drug similar to that in the parental cells (MGH-u 1 sensitive). Controls (without furosemide) continued to show a resistant pattern of fluorescence. In cytotoxicity assays furosemide appeared substantially non-toxic. Resistant cells in the toxicity titration experiments showed increased resistance to levels of furosemide over 500 mug/ml. Parental cells were made only marginally more sensitive against increased background toxicity. CONCLUSION: Furosemide is effective in reversing MDR status in bladder cancer cell lines in vitro. It may also have an increment of intrinsic cytotoxicity, but only at higher concentrations. We propose a potential for further investigation of furosemide as an adjunct to chemotherapy for superficial bladder cancer.

Antibiotics, Antineoplastic↗
PubMed2006

Can lycopene be delivered into semen via prostasomes? In vitro incorporation and retention studies.

Lycopene (C(40) H(56)) is a highly lipophilic antioxidant found in human semen in nanomolar concentrations. It has been shown to be one of the most potent carotenoid antioxidant in various human studies. Prostasomes are organelles secreted by glandular prostatic epithelial cells and are known to play an important role in fertility and prostate cancer. They are also known to possess antioxidant activity and aid the functioning of sperm. We studied the ability of these vesicles to adsorb and retain lycopene into their rich lipid environment in vitro. High-performance liquid chromatography analysis confirmed micrograms of lycopene per milligram of prostasomal protein. In view of the prostasomes' lipid-rich nature it is highly likely that these organelles act as delivery vehicles for this highly lipophilic antioxidant substance into human semen.

Adsorption↗
PubMed2005

The effect of short-chain fatty acids butyrate, propionate, and acetate on urothelial cell kinetics in vitro: potential therapy in augmentation cystoplasty.

The intestinal element of enterocystoplasty is affected by chronic inflammatory changes, which lead to excess mucus production, urinary tract infections, and stone formation. There is also an increased risk of malignancy. These inflammatory changes may be due to diversion colitis, which affects colonic segments excluded from the faecal stream and likewise may respond to intraluminal short-chain fatty acid (SCFA) therapy. The SCFAs have interesting antiproliferative, differentiating, and pro-apoptotic effects, which are protective against colorectal cancer and may influence the risk of malignancy in enterocystoplasty. Before intravesical therapy can be considered, the effect on normal urothelium must be investigated. Primary urothelial cells cultured from biopsy specimens and transformed urothelial (RT112 and MGH-U1) and intestinal cell lines (HT29 and CaCo-2) were incubated with SCFAs. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure the residual viable biomass to assess cell proliferation. Proliferation of primary and transformed urothelial cells in culture was inhibited by all SCFAs in a similar time- and dose-dependent manner. The concentration of SCFA required to inhibit growth of primary cells by 50% (IC50) was 20 mM of butyrate, 120 mM of propionate, and 240 mM of acetate after incubation for 1 h. After 72 h the IC50 was 2 mM of butyrate, 4 mM of propionate, and 20 mM of acetate. Transformed urothelial and colon cancer cell lines demonstrated similar growth inhibition. Butyrate was the most potent inhibitor of cell proliferation, followed by propionate and then acetate. Growth inhibition is not an immediate cytotoxic effect, and urothelial cells show a degree of adaptation to butyrate and growth recovery after incubation with butyrate. In conclusion, butyrate- and propionate-induced growth inhibition is potentially clinically significant and may have therapeutically beneficial implications in vivo.

Acetates↗
PubMed2005

In vitro inhibition of angiogenesis by prostasomes.

Prostasomes are biologically active organelles that are secreted by human prostate epithelial cells, and it is believed that they have a role in prostatic disease. We studied the effect of prostasomes on the human umbilical vein endothelial cell (HUVEC)/Matrigel model of angiogenesis, and the association of labelled prostasomes with HUVECs. The growth inhibitory effect of prostasomes on HUVECs was assayed by spectrophotometric measurement of residual biomass. Preparations of HUVECs on a Matrigel base were exposed to prostasomes, and the development of capillary-like networks was quantified. Prostasomes were labelled with PKH-26, and cultured with HUVECs. Prostasomes were not shown to have a significant effect on HUVEC survival. Angiogenesis assays showed inhibition. The PKH-26-labelled particles were shown to have adhered to the HUVECs. This study adds the inhibition of an in vitro correlate of angiogenesis to the known actions of prostasomes.

Cell Culture Techniques↗
PubMed2005

Differential effects of two cannabinoid receptor agonists on progressive ratio responding for food and free-feeding in rats.

The cannabinoid receptor agonists delta9-tetrahydrocannabinol (delta9-THC) and HU-210 were compared in terms of their effects on: (1) progressive ratio (PR) responding for food, and (2) free food intake. In the first experiment, food-deprived Wistar rats were trained on a time-constrained (60 min) PR-5 schedule for food reinforcement, in which the response requirement incremented by five lever presses for each successive reinforcer. One group of rats received vehicle, 0.5, 1 or 3 mg/kg delta9-THC (i.p.), and three other groups received HU-210 (i.p.) at three different dose ranges, spanning 0.001-0.1 mg/kg. In the second experiment, the effects of the two drugs on free food intake were tested in a separate group of non-deprived rats. For PR responding, delta9-THC significantly increased the break point (final ratio completed) and the total number of lever presses emitted. The same drug also significantly increased free food intake. However, the effects of HU-210 were quite different: it did not alter PR responding at any dose; instead, its only significant effect was to reduce free food intake at 0.06 mg/kg. These data suggest that increased motivation to obtain food might underlie the hyperphagic effects of delta9-THC. However, the synthetic agonist HU-210 has different effects: it only acts to reduce feeding behaviour, an outcome that probably reflects non-specific behavioural disruption. These findings suggest important differences between the two CB1 receptor agonists in terms of their pharmacological effects.

Analysis of Variance↗
PubMed2005

Comparison of disinfectants for biofilm, protozoa and Legionella control.

The aim of this study was to compare the efficiency of different disinfectants applicable to Legionella control in domestic water systems. A domestic water supply simulation unit that allowed simulation of real-world conditions was developed for this purpose. The system, consisting of seven identical rigs, was used to compare treatment efficiency under equivalent conditions of system design, materials, hydraulics, water quality, temperature and initial contamination. During the study, each of six loops received continuous application of one of the following disinfectants: chlorine, electro-chlorination, chlorine dioxide, monochloramine, ozone, or copper/silver. The seventh loop was used as a control and remained untreated. Performance evaluation of these disinfectants was based on their ability to reduce not only Legionella, but also protozoa and biofilms, which contribute to the establishment and dissemination of these bacteria in water systems, and their resistance to treatments. Regarding these criteria, chlorine dioxide and chlorine (as bleach or obtained by electro-chlorination) were the most effective treatments in this study. However, in comparison with chlorine, chlorine dioxide showed a longer residual activity in the system, which constituted an advantage in the perspective of an application to extensive pipework systems.

Animals↗
PubMed2004

Mycophenolate mofetil in pyoderma gangrenosum.

Recently, the use of mycophenolate mofetil (MMF) has expanded in dermatological practice. Three patients with PG received MMF in conjunction with prednisone and a fourth patient received MMF monotherapy daily. MMF in combination with prednisone in three of our patients and alone in our fourth patient induced healing of their ulcers. The first patient tolerated MMF apart from gastrointestinal upset, while treatment in our second patient was complicated by staphylococcal and pseudomonal sepsis. The third patient complained of palpitations and headaches.

Aged↗
PubMed2004

An aqueous formulation of gamma-linolenic acid with anti-proliferative action on human pancreatic cancer cell lines.

Essential fatty acids, especially gamma-linolenic acid (GLA), have been shown to directly inhibit the growth of cancer cell lines in culture. The aim of this study was to see whether an aqueous formulation of GLA works as well as the lithium-based salt. We evaluated the effect of the 1-deoxy-1-methylamino-D-glucitol salt of GLA (MeGLA) on the growth of two human pancreatic cancer cell lines (Panc-1 and MIA PaCa-2) in vitro, and compared its effects with a previously studied formulation, lithium GLA (LiGLA). The effect of time exposure (2-7 days) and difference in concentration (0-1000 micromol/l) were studied using 96-well culture plates. Cell growth was assessed by MTT assay. Control experiments were performed with meglumine alone in similar concentrations. MeGLA had cytostatic and cytotoxic effects on pancreatic cancer cell lines with 50% growth inhibition at 30-100 micromol/l and cytotoxic effects at 60-250 micromol/l. The degree of growth inhibition increased with time of exposure to MeGLA. The anti-proliferative effects of MeGLA were similar to those previously observed with LiGLA. We conclude that MeGLA has equivalent anti-proliferative activity to LiGLA when tested in vitro against pancreatic cancer cell lines and is therefore a suitable alternative to LiGLA for investigation of the in vivo activity of GLA against pancreatic adenocarcinomas.

Cell Division↗
PubMed2004

Master's performance in the New York City Marathon 1983-1999.

BACKGROUND: Physical activity in older people is believed to slow down the natural aging process through its effects on disuse atrophy. OBJECTIVES: To show that elite master (age above 50) male and female athletes, as a group, have improved their running times over the last two decades at a greater rate than their younger counterparts. METHODS: Running time, age, and sex of all 415,000 runners in the New York City Marathon from 1983 to 1999 were examined using linear regression analysis. RESULTS: The number of master participants increased at a greater rate than their younger counterparts (p<0.05). Running times for the top 50 male and female finishers over the past two decades showed significantly greater improvement in the master groups than in the younger age groups (p<0.001). CONCLUSIONS: Participation in the New York City Marathon is increasing at a higher rate in the master groups than in other age groups. Male and female masters continued to improve running times at a greater rate than the younger athletes, whose performance levels have plateaued. This is the largest study to compare master athletic performance with younger counterparts and men with women.

Adolescent↗
PubMed2003

Synergistic activity of gamma-linolenic acid and cytotoxic drugs against pancreatic adenocarcinoma cell lines.

BACKGROUND: Gamma-linolenic acid (GLA) is growth inhibitory both in vitro and in vivo, at doses non-toxic to non-cancer cells. Chemotherapeutic agents have limited activity in pancreatic cancer. Interactions between GLA and cytotoxic drugs have not previously been investigated; any synergy might improve the therapeutic effect of these agents. AIM: To investigate possible interactions between GLA and 5-fluorouracil (5-FU) or gemcitabine against pancreatic cancer cell lines in vitro. METHODS: Two pancreatic cancer cell lines were exposed to GLA alone and in combination with 5-FU or gemcitabine. Residual viable biomass was measured using the MTT assay and the results analysed by the median effect method of Chou and Talalay [Adv Enzyme Regul 1984;22:27-55]. RESULTS: GLA concentrations of 3.9- 125 microg/ml had a synergistic or additive growth inhibitory effect on all tested concentrations of gemcitabine. Synergism was demonstrated between GLA and 5-FU only at concentrations of 62.5-125 microg/ml of 5-FU. CONCLUSION: GLA has a synergistic effect with gemcitabine at concentrations that correspond to in vivo therapeutic doses. GLA with 5-FU is synergistic only at a tight range of high concentrations of 5-FU. GLA lacks toxic side effects and may be useful in combination with gemcitabine.

Animals↗
PubMed2003

Excitation by dopamine of rat subthalamic nucleus neurones in vitro-a direct action with unconventional pharmacology.

Recent anatomical and physiological studies have pointed to a functional innervation of the subthalamic nucleus by dopamine. This nucleus has a pivotal role in basal ganglia function and voluntary movement control and the possibility that dopamine, and dopaminergic medication used in Parkinson's disease, might directly influence its activity is of considerable interest. We have evaluated electrophysiologically the action and pharmacology of dopamine on single subthalamic neurones in rat brain slices. Dopamine increased firing rate to up to a mean of 60% in 98% of the 261 neurones tested when examined using extracellular single-unit recording. This excitation was unaffected by the GABA antagonist picrotoxin, and the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted in a low Ca(2+)/raised Mg(2+) solution, indicative of a direct action, independent of synaptic transmission. Of the 33 cells examined using whole patch-clamp recording, only 13 showed measurable increases in firing rate and/or depolarisations in response to dopamine. Dopamine-responsive cells displayed significantly greater access resistance, suggesting that an unidentified cytoplamic constituent, removed by whole-cell dialysis, was required for the response. Using extracellular recording, the D2-like dopamine receptor agonists quinpirole and bromocryptine, but not the D1-like receptor agonist 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol, also consistently caused an excitation. This was mimicked by the catecholamine releaser amphetamine in 60% of cells tested. However, the dopamine excitation was not significantly reduced either by the D1-like receptor antagonist 7-chloro8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine or the D2-like receptor antagonists (-)-sulpiride, eticlopride and (+)-butaclamol, and the quinpirole excitation was also unaffected by (-)-sulpiride. In contrast, (-)-sulpiride, eticlopride and (+)-butaclamol all abolished the D2-like receptor-mediated inhibition by dopamine of substantia nigra pars compacta neurones. The alpha-adrenoceptor antagonist phentolamine was a weak antagonist of dopamine excitations, but not of those caused by quinpirole. Dopamine excitations also showed weak sensitivity to the 5-HT(2) antagonist ritanserin, but were unaffected by the alpha(1)-adrenoceptor antagonist prazocin and the beta-adrenoceptor antagonist propranolol. The pharmacology of this dopamine excitation is inconsistent with an action on any known catecholamine receptor. However, the effect of amphetamine indicates that an unidentified monamine--possibly dopamine--can be released within the subthalamic nucleus to cause an excitation. The anomalies of its pharmacological characterisation do not strongly support a physiologically relevant direct action of dopamine in the rat subthalamic nucleus.

Amphetamine↗
PubMed2002

Calbindin D-28k positive projection neurones and calretinin positive interneurones of the rat globus pallidus.

Immunohistochemistry for three calcium-binding proteins calbindin D-28k, calretinin, and parvalbumin revealed neuronal heterogeneity within the GP. Each neurone appeared to express either a single type of calcium binding protein or none at all. The co-localisation of calcium binding proteins was not observed. Combined immunohistochemistry and retrograde tract tracing using colloidal gold particles injected into the projection fields, the substantia nigra or subthalamic nucleus, revealed that projection neurones could be labelled with either calbindin or parvalbumin. These cells were of medium size (22 x 12 microm), multipolar and moderate varicose dendritic trees. In contrast, calretinin-positive neurones were never retrogradely labelled, even in regions where neuronal colloidal gold deposits were numerous. This, combined with their rarity (<1%) and small size (11 x 9 microm), suggests that calretinin may be a neurochemical marker for putative rat globus pallidus interneurones. Calcium-binding proteins are known to have unique buffering characteristics that may confer specific functional properties upon pallidal neurones. Indeed, differential calcium binding protein expression may underlie the electrophysiological heterogeneity observed in the rat globus pallidus.

Animals↗
PubMed2002

The effects of meglumine gamma linolenic acid (MeGLA) on an organ culture model of superficial bladder cancer.

The objective of this research was to assess the effects of the novel intravesical drug MeGLA in a physiologically representative model of superficial bladder cancer. Petri dishes were used to culture 5 mm square explants of rat bladder in minimal volumes of supplemented culture medium. Parental and resistant MGH-U1 urothelial cancer cells were transfected with a green fluorescent protein (GFP) vector. Transfectants were purified by flow cytometry. Cells were seeded onto the prepared organ cultures and imaging was performed using confocal microscopy. Confirmation of the tumour colonies was done using scanning electron microscopy. MeGLA was added at various concentrations to the colonies and its effects noted over several days. Results showed that colonies of GFP-MGH-U1 cells established themselves on the explants and could be identified by confocal microscopy. The colonies could then be followed over several days. The colonies were able to survive high concentrations of the drug of up to 1 mg/ml, 400 times the IC > 90% for monolayers and equivalent to doses in clinical use. We conclude that MeGLA is less effective in this system than on monolayer cell lines. However, it showed cytotoxic effects which were comparable to those seen with conventional agents in the same system.

Animals↗
PubMed2002

Intravesical meglumine gamma-linolenic acid in superficial bladder cancer: an efficacy study.

OBJECTIVES: Gamma-linolenic acid (GLA) is known to be cytotoxic to malignant cells. We assessed the efficacy of the novel intravesical formulation, meglumine gamma-linolenic acid (MeGLA), in a phase II trial, in patients with recurrent, superficial bladder cancer. PATIENTS AND METHODS: Thirty patients with recurrent, superficial transitional cell carcinoma (TCC) were recruited. The tumour pattern was recorded at flexible cystoscopy. Patients received a single intravesical instillation of 50ml of either 50mg (1mg/ml) (15 patients), or 125mg (2.5mg/ml) (15 patients) of MeGLA in water, retained for one hour. At subsequent cystoscopy, the tumour patterns were recorded, prior to undertaking routine cystodiathermy. Biopsies were obtained for histological assessment. Responses were divided into complete, partial or none. RESULTS: All 30 patients retained the drug for 1 hour without significant local or systemic side effects. There were 4 (13%) complete responses, 9 (30%) partial responses, and 17 (57%) non-responders. Histology showed no evidence of damage to surrounding urothelium. CONCLUSIONS: Our data confirms the safety and tolerability of MeGLA, which is consistent with findings from a previous phase I trial. A response rate of 43% also indicates that MeGLA has a significant cytotoxic effect against TCC and the results are similar to those obtained using standard, single-dose, intravesical regimens.

Administration, Intravesical↗